Base editing corrects alpha-1 antitrypsin mutation in seven patients

An investigational CRISPR base-editing therapy was used to treat seven patients with alpha-1 antitrypsin deficiency, and liver biopsy findings published in the Journal of Hepatology confirm the underlying SERPINA1 mutation was corrected in one patient. The joint clinical trial, run with Renji Hospital in Shanghai and funded by a Chinese company developing the base-editing method, assessed initial safety and efficacy.

Alpha-1 antitrypsin deficiency is a congenital metabolic disorder caused by a single incorrect DNA base. The faulty alpha-1 antitrypsin protein mainly damages the lungs and liver, and can lead to pulmonary emphysema, liver fibrosis or cirrhosis. Severe cases may require transplantation, and there is no curative treatment.

The team from Hanover Medical School (MHH) targeted the mutation itself rather than delivering an intact copy of the gene. After the defective base was modified, a single-strand break on the opposite strand triggered the cell's own repair program, which inserted the correct counterpart without causing a double-strand break.

Because the disease is common in Europe and the U.S. but uncommon in Asia, MHH sent seven patients to Shanghai accompanied by medical staff. One was Katrin H., a 55-year-old former anesthesiologist diagnosed at MHH in 2011. She had experienced shortness of breath for years and had to give up her job. She had the most severe form, producing no functional protective protein, and received weekly augmentation therapy, but her disease continued to progress. In March she flew to Shanghai, stayed for one month, and was given the gene therapy drug by infusion. Later blood tests found her body was making functional alpha-1 antitrypsin again, she had no side effects, and she no longer needs the weekly protein infusions.

"For me, it's like winning the lottery," she said.

The Journal of Hepatology paper, by Krooss and colleagues, reports that a liver biopsy from one patient showed the SERPINA1 gene was corrected precisely and efficiently by the in vivo base editor. The therapy cannot reverse lung and liver damage that has already occurred, but the patient can hope the condition has been halted.

The treatment has not yet been authorized. MHH plans to continue the clinical trial in early 2027, and Dr. Michael Ott said: "In the long term, this revolutionary approach can be applied to the treatment of other congenital genetic liver diseases where a single base in the DNA needs to be replaced." Alpha-1 antitrypsin deficiency affects an estimated 120,000 people in Europe.